Induction of chromosome-specific aneuploidy and micronuclei in human lymphocytes by metabolites of 1,3-butadiene.

1,3-Butadiene is a carcinogen in rodents, but its potential carcinogenicity to humans remains controversial. Numerous studies have shown that butadiene and its metabolites cause sister chromatid exchanges in vitro and in vivo. To test for other types of genotoxicity, the micronucleus assay and fluorescence in situ hybridization (FISH) have been used to detect chromosome damage in human lymphocytes caused by two reactive metabolites of butadiene, diepoxybutane (DEB) and monoepoxybutene (MEB). DEB (0.5-5.0 microM) significantly increased micronucleus formation 4- to 6-fold (P <0.01) and MEB (1-500 microM) by 2- to 4-fold (P <0.01) over control levels. The ability of DEB and MEB to induce aneuploidy of chromosomes 7, 8, 12, and X was examined using dual-color FISH in both interphase and metaphase cells. These chromosomes were chosen because of their involvement in leukemogenesis. Both DEB and MEB caused dose-dependent increases in hyperdiploidy of chromosomes 12 and X, but had no discernible effect on chromosomes 7 and 8. These results suggest that DEB and MEB cause chromosome-specific aneuploidy in human cells. If formed in sufficient amounts, DEB and MEB may produce chromosome damage of the type found in leukemia following exposure to butadiene.